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FLASH GENE
Symbol RPE65 contributors: shn/mct - updated : 31-07-2011
HGNC name retinal pigment epithelium-specific protein 65kDa
HGNC id 10294
Corresponding disease
CSRD childhood-onset severe retinal dystrophy
LCA2 Leber congenital amaurosis, type 2
RP20 retinitis pigmentosa 20
RP87 retinitis pigmentosa 87 with choroidal involvement
Location 1p31.1      Physical location : 68.894.506 - 68.915.642
Synonym name
  • retinal pigment epithelium-specific protein (65kD)
  • RBP-binding membrane protein
    • Synonym symbol(s) LCA2, RP20, rD12, mRPE65, SRPE65, P63, BCO3
    EC.number 3.1.1.64, 5.2.1.7
    DNA
    TYPE functioning gene
    STRUCTURE 21.14 kb     14 Exon(s)
    Genomic sequence alignment details
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map pter - D1S2806 - D1S2829 - RPE65 - D1S2803 - D1S448 - cen
    RNA
    TRANSCRIPTS type messenger
    text A putative transcription start site lies 54 bp upstream of the initiation codon
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    14 - 2608 63 533 retinal pigment epithelium 1995 7633413
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Visualeye   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier liningretinal pigment epithelium (RPE) specific
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Visualepithelial cell
    cell lineage epidermal keratinocytes
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES globular ,other
    STRUCTURE
    motifs/domains
  • 4 histidine residues involved in iron binding
  • three S-palmitoyl groups
    • mono polymer dimer
    isoforms Precursor a soluble form called sRPE65, and a triply palmitoylated, membrane-bound form known as mRPE65
    HOMOLOGY
    interspecies homolog to beta-carotene 15,15' -monooxygenases
    ortholog to Rpe65, Rattus norvegicus
    ortholog to rpe65a, Danio rerio
    ortholog to RPE65, Pan troglodytes
    ortholog to Rpe65, Mus musculus
    Homologene
    FAMILY
  • beta-carotene dioxygenase family
    • CATEGORY enzyme , structural protein
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic,microsome
    text
  • localized in the RPE smooth endoplasmic reticulum
  • there is a light-dependent change in the distribution of the protein, and that this phenomenon is abolished in the absence of MYO7A function
    • basic FUNCTION
  • is a microsomal protein with isomerase activity in the retinoid visual cycle that playing a role in the isomerisation of all-trans (vitamin A) to 11-cis retinal, the chromophore of the visual pigments
  • isomerohydrolase activity of RPE65 requires coexpression of lecithin retinol acyltransferase (LRAT)
  • retinal pigment epithelial protein essential for the regeneration of 11-cis-retinal, the chromophore of cone and rod visual pigments
  • playing a critical role in retinoid processing in the retinal pigment epithelium
  • may be involved in cellular uptake of retinol which is transported in the bloodstream complexed with plasma retinol-binding protein
  • having isomerohydrolase activity in the retinal pigment epithelium (mutation of any one of the absolutely conserved four histidine and one glutamic acid residues to alanine in RPE65 abolished its isomerohydrolase activity)
  • might be involved in retinoid uptake of keratinocytes
  • adopts functionally and structurally different conformations when bound to lipid bilayers compared with its detergent-solubilized state, although specific changes could not be ascertained
  • iron-dependent, membrane-bound enzyme expressed nearly exclusively in the retinal pigment epithelium (RPE)
  • essential for the function of cone photoreceptors in NRL-deficient mice
  • RPE65 and LRAT play key roles in recycling 11-cis-retinal in the retinal pigment epithelium (RPE)
  • involved in conversion of all-trans-retinyl esters to 11-cis-retinol, required for maintenance of visual function
  • is the retinoid isomerohydrolase that converts all-trans-retinyl ester to 11-cis-retinol, a key reaction in the retinoid visual cycle
  • is essential for both rod- and cone-mediated vision
  • is the isomerase catalyzing conversion of all-trans-retinyl ester (atRE) into 11-cis-retinol in the retinal visual cycle
  • association with the endoplasmic reticulum (ER) membrane is a critical requirement for the catalytic function of RPE65
  • RPE65 is indeed a dynamically-regulated palmitoylated protein and that palmitoylation is necessary for regulating its membrane binding, and to perform its normal visual cycle function
  • RPE65 isomerase plays a pivotal role in photoreceptor survival and function
  • plays an indispensable role in sustaining visual function in vertebrates
  • is likely a palmitoylated protein
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS visual cycle
    PATHWAY
    metabolism vitamin
    signaling sensory transduction/vision
    vitamin A metabolism
    a component
  • protein constituent of major microsomes
  • complexing with LRAT for isomerohydrolase activity
  • dimer is stable even under high ionic strength conditions
    • INTERACTION
    DNA
    RNA
    small molecule
  • RPE65 is an iron(II)-dependent isomerohydrolase and binds an iron ion with a stochiometry of 0,8
    • protein
  • retinol binding protein 4, plasma (RBP4)
  • SLC27A1 markedly inhibits 11-cis retinol production by acting on the production of all-trans retinyl esters and the isomerase activity of RPE65
  • MYO7A and RPE65 appear to be associated with each other, suggesting that MYO7A functions in the localization of the visual cycle enzyme
  • RPE65 activity was reduced by co-expression of fatty acyl:CoA ligases (ACSLs) or SLC27A2
    • cell & other RPE65 associates with membranes through S-palmitoylation of residues Cys231, Cys329 and Cys330 by LRAT
    REGULATION
    Other enzymatic activity of RPE65 requires LRAT coexpression
    phospholipids directly influence RPE65 structure
    ASSOCIATED DISORDERS
    corresponding disease(s) LCA2 , RP20 , CSRD , RP87
    related resource RPE65Mutations
    Retinal Information Network
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in actinic keratosis
    tumoral     --low  
    in invasive squamous cell carcinoma
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
  • A recombinant adeno-associated virus (AAV) carrying wild-type RPE65 (AAV-RPE65) restores visual function in the naturally RPE65-/- dog model suffering from early and severe visual impairment similar to that seen in human LCA
  • Early oral administration of 9-cis-retinal in Rpe65-deficient mice leads to rapid restoration of visual pigment and function
  • Injection of rAAV-mediated RPE65-gene transfer to the retina of the naturally RPE65-/- dog model leads to a long-term restoration of rod and cone vision
  • RPE65 gene replacement studies have short term safety safety and show an improvement in visual function in humans harbouring RPE65 mutations and suffering from advanced stages of LCA and
  • Lentiviral mediated RPE65 gene replacement restores visual function in Rpe65 deficient mice
  • Early administration of 9- or 11-cis retinal can partially prevent cone loss in the Rpe65-/- mouse
    • ANIMAL & CELL MODELS
  • A homozygous four nucleotide (AAGA) deletion in the RPE65 gene in a form of retinal dystrophy in dogs of the Swedish Briard breed. Dogs show prominent RPE inclusions and slightly abnormal rod photoreceptor morphology early in life, and slowly progressive photoreceptor degeneration. Photoreceptors are slightly disorganized at the posterior pole and equator. ERG analysis revealed severely decreased rod and cone responses
  • Rpe65 deficient mice exhibit changes in retinal physiology and biochemistry: outer segment discs of rod photoreceptors are disorganized, rod function is abolished and cone function remains, lack of rhodopsin but no opsin, over-accumulation in the RPE of all-trans-retinyl esters
  • In aged Rpe65-/- mouse, opsin levels decrease because of the loss of photoreceptors but the remaining opsin is structurally intact, and the components of the phototransduction cascade and the retinal circuitry remain functional
  • In the Rpe65-/- mouse the expression of cone-specific genes is downregulated at early ages leading to cone photoreceptors degeneration
  • rd12 mice, a natural model for human RPE65 mutations, exhibit small punctate white spots on fundus examination at 5 months of age, no RPE65 expression, 11-cis retinal, or rhodopsin, accumulation of retinyl esters in the retinal pigment epithelium. First sign of retinal degeneration was detected at the electron microscopic level around 3 weeks of age
  • Circadian phase shifting responses in Rpe65(-/-) mice are attenuated and the number of melanopsin-immunoreactive perikarya and the extent of dendritic arborizations are decreased
  • adult canine RPE65 model displays altered expression of cone arrestin and delocalization of rod opsin, outer nuclear bipolar cells sprouting of the dendritic arbors toward the outer nuclear layer and retraction of their axons in the inner nuclear layer (